DESCRIPTION: (Applicant's Abstract) Nicotine exerts complex behavioral effects on both humans and animals, and in addition to having reinforcing or rewarding qualities it has also been reported to be anxiolytic, to have effects on arousal and to act as a cognitive enhancer. The goal of this project is to determine where in the brain nicotine acts to exert its cognitive effects. This work will use knock out mice lacking the b2 subunit of the neuronal nicotinic acetylcholine receptor (nAChR) as subjects for neurochemical and behavioral testing. These mice have been shown to be insensitive to the effects of nicotine on the test of passive avoidance, and to perform differently than their wild type siblings on this test even in the absence of pharmacological treatment. We will also generate new lines of transgenic mice in which the b2 subunit is expressed only in specific brain areas. These mice will be used as tools to investigate the anatomical requirements for the high affinity receptor in learning paradigms. The first goal of this project will be to determine whether brain areas are differentially activated in response to avoidance training in b2 mutant and wild type mice in the presence or absence of nicotine treatment. We will also determine whether a7nAChRs or muscarinic receptors are more or less active during passive avoidance training in the absence of the b2 containing high affinity nicotine receptor. Transgenic mice that over express either the beta2 or the beta4 subunit of the nAChR in specific brain regions will be generated and crossed mice lacking the high affinity receptor for nicotine. This will result in lines of mice that express this receptor only in particular brain regions in response to treatment with tetracycline. These experiments will allow a molecular dissection of the effect of nicotine on a cognitive task, and will provide information on both the temporal and anatomical loci of the action of nicotine in the brain.